Drug delivery systems and methods

ABSTRACT

The present invention relates to a drug delivery device for mixing and delivering a drug by injection. The device includes a housing having a first port or opening therein that receives a first container that contains a fluid or powdered drug, for example a lyophilized drug. The housing can also include a second port or opening that receives a second container that contains a fluid to be mixed with the drug to form an injectable fluid. The device includes a manifold having a channel that fluidly connects the first and second containers. A penetrating membrane such as a needle is used to inject the drug into a patient which is in fluid communication with the first container. The needle is movable from a storage position in the housing to an injection position extending through the housing.

RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 09/439,963, now U.S.Pat. No. 6,478,771, filed on Nov. 12, 1999, which claims priority toU.S. Provisional Application No. 60/108,382 filed Nov. 13, 1998 and U.S.Provisional Application No. 60/131,644 filed Apr. 29, 1999, the entireteachings of all of these applications being incorporated herein byreference.

BACKGROUND OF THE INVENTION

The present invention relates to the preparation and administration of aproduct and, more particularly, to the injection of the same into aliving organism, for example, a human body.

Previously, various devices have been developed for the percutaneousdelivery of medications into living organisms including syringes inwhich a liquid is delivered from a chamber using pressure asserted by amanual plunger through a needle inserted under the skin.

Additionally, it is well known in the art that the storage life ofcertain injectable substances such as glucagon, used to dissolve bloodclots, is increased when the substance is stored in a powdered orlyophilized state, for example. These lyophilized substances (i.e.,drugs or compounds) are presently used for injection of materials thatwould otherwise be unstable. Lyophilization, for example, is the rapidfreezing of a material at a very low temperature followed by rapiddehydration by sublimation in a high vacuum. The resulting lyophilizedcompound is typically stored in a glass vial or cartridge which isclosed by a cap, such as a rubber stopper or septum.

It is necessary to reconstitute the powdered or solid material, such asa lyophilized compound, prior to administration. This is accomplished bymixing the solid compound with a suitable diluent or liquid.Reconstitution typically involves the use of a syringe with a needle towithdraw the diluent from a separate vial and inject it into the vialcontaining the compound. The compound is then thoroughly mixed,typically by shaking the vial by hand, and a separate syringe with aneedle withdraws the desired amount to be injected into the patient.Because two separate containers are used, the person reconstituting thecompound must be certain to mix the correct amounts such that a properconcentration of the mixture results. When a syringe is used to mix thediluent and drug, the exact volume of diluent to drug ratio is difficultto obtain. Thus, precise concentration levels of administered drug maybe compromised.

Moreover, because the diluent and compound are in separate, sterilizedcontainers, the manual withdrawal of diluent via a syringe andreinjection of the same into the container containing the solid materialsuch as a powdered or lyophilized drug may compromise sterility, andsafety due to the use of a syringe.

Because of increased use of powdered compounds or lyophilized drugs, forexample, it is desirable to provide both professional andnon-professional personnel with a reconstituted drug delivery system. Itis desirable to have a simple, reliable system that facilitatespreparation and safe delivery of an accurate dosage of a reconstitutedcompound. In addition, it is desirable to provide a system thatreconstitutes a lyophilized drug while maintaining sterility throughoutthe process. Also, it is desirable to provide improvements in thepercutaneous delivery of medication generally, which provide for safe,effective administration by the user.

SUMMARY OF THE INVENTION

The present invention relates to systems and methods for deliveringliquid drugs to a user. The drug delivery system can include delivery ofreconstituted powdered drugs such as, for example, lyophilized drugs, ormore generally for the transfer and delivery of liquid drugs. Powderedor lyophilized drug delivery further includes a system to reconstitutethe powdered drug. The drug delivery systems may further include apressurization system which pressurizes the drug for transfer to adelivery system or for direct subcutaneous delivery. Further, the drugdelivery system in accordance with the present invention includes aninjector system which contacts the tissue and delivers the drug to thepatient or user. In the alternative, the drug delivery system inaccordance with the present invention includes filling of detachabledelivery devices, for example, a standard syringe, a needlelessinjector, an infusion device or different types of pumps. Anotherexample uses a pen injector which aspirates the liquid drug from thesystem and in turn delivers the drug subcutaneously.

The methods for delivering a powdered drug such as a lyophilized druginclude the steps of pressurizing a diluent solution in a diluent vial.The pressurizing systems may include, but are not limited to, acompressed air supply, a chemical gas generator, a collapsible volumesupply, a bellow canister, a standard syringe or a cylinder, forexample. The methods further include the step of delivering thepressurized diluent solution to the powdered drug vial. The next step inthe method includes the reconstitution of the drug to form a liquid drugby mixing the powdered drug with the diluent solution. The methodsfurther include the steps of providing the liquid drug to an injectorsystem or transferring the liquid drug to detachable delivery devices.The following step includes the injection of the liquid drug into thetissue of the patient or user. The methods further include the steps ofmoving the injection needle from a delivery or injection position to aretracted or storage position once delivery is complete. It should benoted that, depending on the application or delivery of differentmedicaments, the features of the drug delivery systems may vary. Forexample, the pressurization level can vary depending upon the viscositylevel of the medicament, and the needle type or length can varydepending upon subcutaneous injection or intermuscular injection. Forexample, for subcutaneous injections, the needle length ranges from 5 to12 mm while the needle length may vary up to about 3 cm forintermuscular injections.

The methods for delivering a liquid medicament to a patient include thesteps of pressurizing the liquid drug solution in the vial with apressurizing system. The subsequent steps are similar to the stepsdescribed with respect to the methods for delivering a powderedmedicament.

A preferred embodiment of the present invention features an injectorsystem having an angled or u-shaped needle. Another preferred embodimentof the present invention features an injector system having a straightneedle. Yet another preferred embodiment of the present inventionemploys a transfer system for transferring the drug to delivery devicessuch as, for example, a standard syringe with a needle or a needlelesspen injector. The devices receive the liquid drug from a container, suchas a vial containing the liquid drug. The delivery devices subsequentlydeliver the medication to the user's tissue as described herein.

Another preferred embodiment of the present invention features acombination system having the ability to reconstitute drug into solutionand subsequently inject it into a user. In accordance with thisembodiment the reconstituted drug delivery system has a housing having afirst opening or port that receives a first container that contains asolid substance, such as a powdered lyophilized drug, for injection. Itshould be noted that the container is a rigid container, such as, forexample, a vial or a cartridge containing the powdered drug. The housingcan also include a second opening or port that receives a secondcontainer that contains a fluid to be mixed with material in the firstcontainer, to form an injectable fluid. The drug delivery system mayinclude a manifold having a first channel that provides fluidcommunication between the first and second containers. The manifoldfurther includes a second channel between the first container and adelivery or transfer device. The manifold can also include acommunication channel to a pressurization system which provides thedriving pressure to deliver the liquid drug. In a preferred embodiment,the penetrating member is a needle, in fluid communication with thefirst container after the needle moves between a storage position in thehousing to an injection position extending outside the housing and intothe user.

A preferred embodiment of the invention provides for concealment of theinjection needle within the main housing of the drug delivery deviceexcept during the injection of the drug to the user. This embodiment caninclude a needle retraction device for withdrawing the needle into thehousing after injection to minimize the risk of exposure to acontaminated needle.

In accordance with other aspects of the present invention, the length ofthe delivery path from the container with the injectable fluid to theinjection needle is reduced to minimize loss of residual amount ofliquid drug. According to another aspect of the invention, the injectionneedle first pierces the skin of the person being injected and isconcurrently placed in fluid communication with the first container thatcontains the injectable fluid. According to yet another aspect of theinvention, the container that contains the injectable fluid issubstantially visible during reconstitution and injection such that theuser can visually observe the process. A compressed fluid, such as a gasin the container with the injectable fluid, is used to force theinjectable liquid through the injection needle and into the tissue beinginjected. In an alternative embodiment, the device has a single portwith a compression element such that a container with a liquidmedication, such as a previously reconstituted material, can be insertedinto the housing and simultaneously pressurized to the needed pressureto deliver the correct dose over a predetermined time period.

In a preferred embodiment of the system, the device is used with theinjectable fluid container being vertically oriented during injection.To reduce the risk of injecting any gas into the injection site, a gasimpermeable membrane such as a hydrophilic membrane is disposed in thefluid path, which in a wetted state minimizes or preferably prevents gasflow while allowing liquid to flow through the membrane. The rigidcontainers need to be in a vertical orientation during reconstitutionfor appropriate pressurization. In an embodiment including a cartridgehaving diluent and air, a vertical orientation is not required forreconstitution. According to a further aspect of the present invention,the axis of the injection needle is perpendicular to the longitudinalaxis of the container with the injectable fluid. In a preferredembodiment, the containers containing a powdered or lyophilized drug anddiluent are inserted in the housing in the same direction along parallelaxes. In another embodiment, the containers are inserted along a commonaxis or parallel axes in the opposite direction. The system can havehousing apertures, ports, or openings that have a size compatible withstandard vial and cartridge sizes such that existing vials and/orcartridges can be used. The container contents do not have to be mixeduntil immediately prior to injection. Because the contents of thecontainers are only in contact with other sterile parts, sterility priorto and during the reconstitution process is maintained.

According to another aspect of the present invention a furtherimprovement to reduce and preferably prevent the risk of injecting gasinto the injection site, includes the use of a drug which is gasimpermeable once wetted. Further, since the gas impermeable membrane cansustain pressure, the delivery time for the liquid drugs is shortened asa higher driving force is generated using pressurization systems. Bydisposing such a membrane such as a hydrophilic membrane in the drugdelivery path that is gas impermeable in a wetted state, gas needed tocontrol injection pressure and duration can be added in the system asthe membrane checks the delivery of gas to the user. The containercontaining the fluid can be a changeable volume container which containsa controllable volume of a gas, for example, air. This controllablevolume of air and/or fluid are forced into the drug container, resultingin a drug under pressure to deliver the correct dose over a selectedtime period. According to a further aspect of the invention, the deviceincludes a manifold system to minimize the drug delivery path andsimplify assembly costs, and increase system reliability. The simplicityand flexibility of the manifold system facilitates the use of standardprefilled cartridges and syringes. In a preferred embodiment, themanifold is a two-piece polycarbonate molding in which the two moldedelements are ultrasonically welded together. The gas impermeablemembrane is attached or welded to one piece of the polycarbonatemolding.

According to another aspect of the present invention, a furtherimprovement to deliver an accurate predicted volume of a drug includesadjustable height penetrating members, such as, for example, outletspikes. In the alternative, delivery of an accurate predicted volume,for example 50% or 80% etc., can be gauged from the residual drug volumeor the use of detachable delivery devices, for example, a standardsyringe or a pen-type pump injector.

According to another aspect of the present invention, a furtherimprovement to the drug delivery systems includes interlocks andindicators which ensure the safe and accurate delivery of the drugs. Theinterlocks include, but are not limited to latches which provide for adesired sequence of operation such as pressurization of containers tofollow the step of insertion of the containers, or prevention ofdisplacement of the needle to an injection position after a firstinjection use. The indicators include a vertical orientation indicatorand end of delivery indicators.

According to another aspect of the present invention, the housing of thedrug delivery device is shaped and designed to function appropriately toenable single handed operation. For example, the bottom surface of thehousing is flat in shape to allow table top placement to accommodatesingle handed operation by the user. Further, the device is sized toenable the insertion of vials and subsequent activation of the deviceusing one hand.

In a preferred embodiment, the system housing is lightweight andcompact, having a weight of less than 30 grams and a volume of less than100 cm³. This provides a portable disposable device that can bediscarded or recycled after a single use and that is readily transportedby the user. In addition, the present invention is self-contained andmaintains sterility throughout the reconstitution and injection of afluid such as a lyophilized drug. It should be noted, the weight andvolume of the system housing can vary depending upon the differentembodiments and the volume of drug being delivered to a user.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1F illustrate the operation of a preferred embodiment of a drugdelivery device in accordance with the present invention.

FIGS. 2A and 2B illustrate cutaway views of the drug delivery deviceshown in FIGS. 1A-1F, along line 2A, 2B-2A, 2B in FIG. 1F.

FIGS. 3A-3D illustrate the sectional views of the internal components ofthe drug delivery device of FIGS. 1A-1E and FIG. 2 during administrationof the reconstituted drug.

FIGS. 4A-4O illustrate the operation of a preferred embodiment of a drugdelivery device in accordance with the present invention.

FIGS. 5A-5C are perspective views of a preferred embodiment of a drugdelivery device in accordance with the present invention.

FIGS. 6A-6C illustrate the operation of a drug delivery devicesubstantially similar to the device shown in FIGS. 5A-5C.

FIGS. 7A-7C are partial perspective views of the drug delivery device ofFIGS. 5A-5C and 6A-6C illustrating the injection of the drug.

FIGS. 8A-8F illustrate the operation of a drug delivery devicesubstantially similar to the device shown in FIGS. 5A-5C.

FIGS. 9A-9F illustrate the operation of a preferred embodiment of a drugdelivery device in accordance with the present invention.

FIGS. 10A and 10B are graphical illustrations of the pressure, weight,and delivery characteristics of a preferred embodiment of the invention.

FIGS. 11A-11D illustrate cutaway views of an alternative embodimentincluding a drug container subassembly of the drug delivery device inaccordance with the present invention.

FIGS. 12A-12B illustrate perspective views of a preferred embodiment ofthe diluent container subassembly shown in FIGS. 11A-11D.

FIGS. 13A and 13B illustrate cutaway views of an alternate embodiment ofthe drug delivery device in accordance with the present invention.

FIG. 14A illustrates a cutaway view of another preferred embodiment ofthe drug delivery device in accordance with the present invention.

FIGS. 15A and 15B illustrate cutaway views of an alternate embodiment ofthe drug delivery device in accordance with the present invention.

FIG. 16 illustrates a cutaway view of an injection device in accordancewith the present invention.

FIGS. 17A-17C illustrate cutaway views of an alternate embodiment of thedrug delivery device in accordance with the present invention.

FIGS. 18A-18C illustrate cutaway views of an alternate embodiment of theinjector system of the drug delivery system in accordance with thepresent invention.

FIGS. 19A-19F illustrate alternate embodiments of pressurization systemsincluded in the drug transfer system in accordance with the presenttransfer invention.

FIGS. 20A-20C illustrate views of an alternate embodiment of the drugdelivery system in accordance with the present invention which usesstandard vials containing a liquid medicament.

FIG. 21 illustrates a view of another preferred embodiment of the drugdelivery system in accordance with the present invention which usesstandard vials containing a liquid medicament.

FIGS. 22A-22E illustrate cutaway and perspective views of an alternateembodiment of the drug delivery system in accordance with the presentinvention.

FIGS. 23A and 23B illustrate alternate preferred embodiments to controlthe dose of drugs in accordance with the present invention.

FIGS. 24A-24C illustrate cutaway views of an alternate embodiment of thedrug delivery system in accordance with the present inventionincorporating filling devices, for example a syringe, to inject the drugsystem.

FIG. 25 illustrates a cutaway view of an alternate embodiment of thedrug transfer system in accordance with the present inventionincorporating filling devices, for example a pen type pump to inject theliquid medicament.

FIGS. 26A-26D illustrate perspective views of a preferred embodiment ofa drug transfer system in accordance with the present invention.

FIGS. 27A-27C illustrate cutaway views of a preferred embodiment of adrug delivery system in accordance with the present invention.

FIGS. 28A-28C illustrate cutaway views of the operation of a preferredembodiment of a drug delivery system in accordance with the presentinvention.

FIG. 28D illustrates an enlarged cutaway view of a preferred embodimentof the spike which brings the liquid drug in communication with thedelivery system in FIGS. 28A-28C.

FIGS. 29A and 29B illustrate partial cutaway views of a preferredembodiment of the drug transfer delivery system in accordance with thepresent invention.

FIGS. 30A and 30B are views showing the two piece construction of themanifold in accordance with the drug delivery system of the presentinvention.

FIGS. 31A-31G are perspective views of a preferred embodiment of a drugdelivery system in accordance with the present invention.

FIGS. 32A-32E are perspective views of another preferred embodiment of adrug delivery system in accordance with the present invention.

FIGS. 33A-33I are cutaway views illustrating the interlocks built intothe drug delivery system in accordance with the present invention.

FIGS. 34A-34D are views of a preferred embodiment illustrating an end ofdelivery indicator of the drug delivery system in accordance with thepresent invention.

FIG. 35 is a graphical illustration of a delivery profile of a preferredembodiment of the drug delivery system with no additional volume of airin the liquid vial in accordance with the present invention.

FIG. 36 is a graphical illustration of the delivery duration anddelivery pressure of a preferred embodiment of the drug delivery systemin accordance with the present invention.

FIG. 37 is a graphical illustration of delivery parameters of injectinga drug with no additional volume of air in accordance with the presentinvention.

FIG. 38 is a graphical illustration of the air pressure gradient on ahydrophilic membrane in the drug delivery system in accordance with thepresent invention.

FIG. 39 is a graphical illustration of the delivery profile with respectto time for a vial system containing about 7.5 ml of air in accordancewith the present invention.

FIG. 40 is a flowchart describing the method of delivery of areconstituted drug in accordance with the present invention.

FIG. 41 is a flowchart describing the method of delivery of a liquiddrug in accordance with the present invention.

The foregoing and other objects, features, and advantages of the drugdelivery systems and methods will be apparent from the following moreparticular description of preferred embodiments of the invention, asillustrated in the accompanying drawings in which like referencecharacters refer to the same parts throughout the different views. Thedrawings are not necessarily to scale, emphasis instead being placedupon illustrating the principles of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to drug delivery systems and methods.The drug delivery system provides generally for the delivery of a drugin solution under pressure, and more particularly to the injection ofpowdered or lyophilized drugs that require reconstitution. The drugdelivery system includes a reconstitution system, a pressurizationsystem to facilitate drug delivery, a transfer system and an injectorsystem. Different embodiments of the present invention may use only oneof the systems described and other embodiments can employ combination ofthese systems, depending on the requirements of different applications.For example, a preferred embodiment can deliver a liquid drug and notrequire reconstitution. Therefore the drug delivery systems and methodsare a combination of some or all of the systems or processes describedbelow.

With reference to FIGS. 1A-1E, the general operation of a preferredembodiment of a drug delivery device 100 is illustrated. FIGS. 2A-2B,and 3A-3D provide sectional views of the same embodiment for clarity. Asspecifically illustrated in FIG. 1A, drug delivery device 100 comprisesa first member or housing 304 and a pivotally connected second member orhandle 106. The device 100 is used to mix, within a sterilizedenvironment, a first liquid such as a diluent 166 (for example, a fluidsuch as sterilized water) with a second powdered drug such as alyophilized drug or compound concentrate 164, e.g., interferon, and toinject the resulting reconstituted lyophilized drug into a livingorganism, which in the preferred embodiment is a human being.Advantageously, the device 100 utilizes a standard vial or first storagecontainer 102, which contains the lyophilized drug or compound 164, anda standard cartridge or second storage container 116, which contains thediluent 166. The device 100 may be formed from inexpensive materials,such as plastic or the like, such that it is economically feasible todispose of the device after a single injection.

In preparation for the administration of the drug, the user removesprotective packaging which envelops the device 100. This packagingmaintains sterility of the device 100 prior to use. In the preferredembodiment of the invention, cartridge 116 containing diluent 166 comespreassembled, being locked into the bottom of housing 304 by the arms133 as shown in FIGS. 2A and 2B.

The sterility protector of the vial 102 is removed and then locked intothe top of housing 304 as shown in FIG. 2A with a needle 124 from thehousing penetrating a stopper 112 of the vial. At this stage, vial 102is filled with air at ambient pressure. The cartridge 116 is pushedupward, i.e., toward vial 102. The cartridge 116 is punctured and thediluent 166 is delivered to the vial 102 as shown in part in FIG. 1C. Atthis stage, as will be explained below, there is a fluid such as gas invial 102 which is compressed by transfer of diluent 166 into vial 102.The user swills the device 100 to ensure the lyophilized drug isappropriately reconstituted. The reconstituted lyophilized drug, orinjectable fluid, is identified as reference number 160.

Now, drug in solution with the diluent is ready for injection. Thedevice 100 is pressed against the skin of the person to be injected withthe vial 102 in a vertical orientation to ensure that the compressedgas, for example, air is used to inject the reconstituted drug and thatthe gas or air is not injected into the injection site. The user pressesthe handle 106 which causes the injection needle 130 to move between afirst position, or storage position, within the housing 304 as shown inFIG. 3A, and a second position, or injection position, outside thehousing as shown in FIG. 3C. It is preferred that the needle extend outof the housing 304 in the range of 5 to 12 millimeters. The secondextended position of the injection needle 130 is also illustrated inFIG. 1D. At this point, the injection needle 130 is fluidly connected tovial 102 such that the reconstituted lyophilized drug 160, underpressure from the compressed gas in vial 102, is delivered to theinjection site. The delivery of the reconstituted lyophilized drug 160can be completed in a time period in the range of 10-30 seconds.

Upon release of handle 106, a biasing mechanism 108 (to be detailedbelow) returns the handle to the original position. Simultaneously, aneedle retraction mechanism (also to be described below) locks theinjection needle 130 within the housing 304, thereby reducing andpreferably preventing exposure of the contaminated needle. The finalstage of operation is illustrated in FIG. 1E, wherein the device 100 maybe safely discarded.

FIG. 1F is a view taken along line 1F—1F of FIG. 1E and illustrates therelative positions of vial 102 and cartridge 116 in housing 304. Asshown, the longitudinal axes of vial 102 and cartridge 116 are parallelbut offset relative to the positioning within the housing 304. Thisallows for both vial 102 and cartridge 116 to be inserted into thehousing 304 without interfering with the internal components of thedevice 100, for example, the needle retraction mechanism describedbelow.

FIGS. 2A and 2B illustrate cutaway views along lines 2A, 2B—2A, 2B ofFIG. 1F of the device 100 including vial 102 and cartridge 116. Moreparticularly, vial 102 is preferably a standard vial, for example, a 2milliliter vial, which typically comprises glass and includes apuncturable rubber stopper 112 held in place by an aluminum band orother sealing mechanism 114. The upper end of housing 304 includes agrooved portion 132 which locks the vial 102 to the housing by passingthe lip of the aluminum band 114 under a pair of spaced apart arms thathook up into the housing. A first needle 124, or other suitable means,is mounted to the housing 304 and is configured to pierce the rubberstopper 112 of vial 102 upon insertion of the vial into the lockingposition provided by arms 133. First needle 124 is fluidly connected toa first channel or tube 122 for receiving the diluent from cartridge 116as illustrated in FIG. 2B. Cartridge 116, similar to vial 102,preferably comprises a standard cartridge (for example, a 2 millilitercartridge with about 1 milliliter diluent) and includes a rubber stopper118 which is pierced by a second needle 126, or other suitable means.Second needle 126 is fixedly mounted on an extending member orcompression element 238 of housing 304 such that the cartridge ispierced upon insertion of the cartridge. First tube 122 is fluidlyconnected to the second needle 126. Upon insertion of the cartridge 116,extending member 238 or compression element of housing 304 contacts andpushes rubber stopper 118 toward the bottom of cartridge 116. In thismanner, the diluent 166 is forced up tube 122 into vial 102 to mix withthe drug 164 contained therein. In the preferred embodiment of thepresent invention, cartridge 116 contains approximately 1 milliliter ofdiluent which is forced into vial 102, resulting in a pressure insidevial 102 of approximately 2.25 bars. This pressure can be adjusted, forexample, by decreasing the amount of diluent or air in cartridge 116. Ahigher pressure inside vial 102 injects the reconstituted drug 160 morequickly.

Thus, a sterilized solution is provided wherein the diluent 166 is mixedwith the lyophilized drug 164 with minimal exposure to outsidecontaminants. It is preferable that vial 102 containing thereconstituted lyophilized drug 160 be visible during reconstitution andinjection such that the user can properly visually verify that thelyophilized drug 160 is thoroughly mixed with diluent 166 and that thevial 102 is vertical during injection to ensure the compressed gas isnot being injected into the injection site.

Handle member 106 is pivotally connected to the housing 304 at a firstend by a pivoting mechanism 110 which can include a rivet or othersuitable means such that the handle member rotates in the direction ofarrow 240. Handle member 106 includes biasing mechanism 108 whichresiliently biases handle member such that the end opposite thepivotally connected end is forced away from housing 304. Biasingmechanism 108 includes an extending member from handle member 106 whichcontacts housing 304, thereby providing a resilient biasing force awayfrom the housing when the handle member is forced toward the housing.Alternatively, or additionally the biasing mechanism 108 can comprise aconventional spring, or other suitable means, interposed between housing304 and handle member 106 which provides the biasing force.

Also shown in FIG. 2A is a needle injection and retraction mechanism forinjecting the reconstituted drug 160 into the person and retracting theinjection needle 130 within the housing 304. The mechanism includes afirst bar member 140, which is pivotally connected at a first end bymember 136, and guidably mounted at a second end to the handle member106 by a first coupling device 142, such as a pin, rivet, bolt, or othersuitable means. Member 136 fixedly supports injection needle 130 and isguided by an opening 138, or needle aperture, in the housing 304. In thepreferred embodiment of the invention, injection needle 130 is in therange of a 24-28 gauge needle. The movement of first coupling device 142is controlled by a J-shaped slot 134 which can comprise a slot or groovein handle member 106. A second bar member 148 is pivotally connected ata first end to first coupling device 142 and pivotally connected at asecond end to a third bar member 152 by a third coupling device 150.Third bar member 152 fixedly supports a third needle 128 and may beguided by internal bore in housing 304. A second channel or tube 120fluidly connects the third needle 128 and injection needle 130. It ispreferable to minimize the length of tube 120 such that the residualvolume of drug remaining in the tube after injection is reduced toincrease the accuracy of the dosage.

The operation of drug delivery device 100 shown in FIGS. 2A and 2B isillustrated in FIGS. 3A-3D. FIG. 3A illustrates the stage at which thecartridge 116 is inserted forcing diluent 166 up tube 122 into vial 102.It will be recalled that the rubber stopper of 118 of cartridge 116 isforced to the bottom of the cartridge by member 238 as shown in FIGS. 2Aand 2B. This causes the diluent 166 to be forced up tube 122 whichresults in the reconstituted drug 160 being under pressure, which in thepreferred embodiment is approximately 2.25 bars. The device 100 ispreferably vigorously shaken to ensure the lyophilized drug is properlymixed with diluent 166.

In FIG. 3B, the device 100 is placed against the skin of the personbeing injected. The user presses handle member 106 toward the housing304 in a direction shown by arrow 240A, thereby displacing injectionneedle 130 from the first position within the housing to a secondposition outside the housing such that the needle penetrates the skin ofthe body being injected.

As shown in FIG. 3C, continued pressure of the handle 106 towards thehousing 304 causes the first bar member 140 to ride up the J-shaped slot134. Simultaneously, second bar member 148, which includes a linear slot244, is rotated such that first coupling device 142 rides up to the topof slot 244.

FIG. 3D illustrates the continued pressing motion of the handle member106 toward the housing 304. As the handle member 106 continues to pivot,the second bar member 148 forces third bar member 152 and hence thirdneedle 128 upward such that third needle penetrates the rubber stopper112 of vial 102. Because the reconstituted lyophilized drug 160 is underpressure, it is forced through tube 120 and thus into the person beinginjected. At this point, biasing mechanism 108 is compressed. As thehandle member 106 is released, biasing mechanism 108 forces the handlemember away from the housing 304 as indicated by arrow 240B and thuswithdraws injection needle within the housing. This is illustrated inFIG. 3D. J-shaped slot 134 is beneficially provided with an end lockingportion 146 which catches coupling device 142 such that the injectionneedle 130 is “locked” within the housing 304 after a single injection.Now, the device 100 can be safely discarded.

FIGS. 4A-4K illustrate a drug delivery device 100-1 in accordance with apreferred embodiment of the present invention wherein the same referencenumbers refer to the same or similar elements. More particularly, FIG.4A illustrates the device 100-1 which includes a housing 304-1 having afirst port or opening 176 for receiving a diluent cartridge 116 and asecond port or opening 262 for receiving vial 102. In this embodiment,it is preferred that cartridge 116 containing diluent 166 bepreassembled such that the cartridge is partially penetrated by needle126-1 and such that the device 100-1 (without vial 102) is wrapped by apackaging material to maintain sterility prior to use. Again, it ispreferable to use a standard 2 milliliter vial and cartridge thatcontains 1 milliliter of diluent. Thus, the user unwraps the packagingmaterial and places vial 102 containing the lyophilized drug 164 intothe opening 262. Alternatively, vial 102 and cartridge 116 are packagedseparately from the device 100-1 as shown in FIG. 4A. The user removesthe sterility protector and presses the vial 102 firmly into the openinguntil needle 124-1 penetrates the rubber stopper 112. The user thenforces cartridge 116 into the housing 304-1. As cartridge 116 is forcedinto the housing 304-1, the rubber stopper 118 is first penetrated byneedle 126-1 such that the needle extends into the diluent 166. Thisstage is illustrated in FIG. 4B.

Continuing to insert the cartridge 116 into the housing 304-1 forces therubber stopper 118 to the bottom of the cartridge, as shown in FIG. 4C.That is to say, the first opening 176 of housing 304-1 is preferablycircular, thereby allowing the walls of cartridge 116 to enter thehousing and not the rubber stopper 118. This forces the diluent 166through needle 126-1 to a manifold or communication passageway 168 andinto the vial 102. Again, the resulting reconstituted lyophilized drug160 in vial 102 is preferably under pressure of about 2.25 bars. Agreater or lower pressure may be necessary depending on the volume to beinjected. The device 100-1 is preferably vigorously shaken to ensure thereconstituted lyophilized drug 160 is properly mixed in preparation forinjection.

It is preferable to insert vial 102 containing the lyophilized drug 102before insertion of cartridge 116 containing diluent 166 such that thediluent is not spilled into opening 262. In order to ensure the properinsertion sequence of vial 102 and cartridge 116, an interlockingmechanism is provided in accordance with another aspect of the presentinvention. Interlocking mechanism comprises a bar member 266 pivotallyconnected to the housing 304-1 between the openings 176 and 262. The barmember is configured to be moved in the direction of arrow 264 (FIG. 4A)upon insertion of vial 102. Thus, as shown in FIG. 4A, bar member 266prevents cartridge 116 from being inserted. As vial 102 is inserted, itrotates bar member 266 in the direction of arrow 264

As shown in FIG. 4B, the device 100-1 is further provided with anactuator or pushing member 174 for displacing the injection needle 130-1between a first position within the housing 304-1 and a second positionoutside the housing. It is preferred that the injection needle 130-1extend out of the housing 304-1 in the range of 5-12 millimeters. Theinjection needle 130-1 is in the range of a 24-28 gauge needle and ispreferably a “U” type needle forming a channel 131 and having a secondend 172 configured to puncture sealing member 170. Sealing member 170,which can be any puncturable material such as butyl rubber, sealinglymaintains the liquid in the upper part of housing 304-1 prior to use.

It is preferable to prevent displacement of the injection needle 130when the device 100-1 is not properly oriented, for example, upsidedown, in order to prevent the compressed gas in vial 102 from beinginjected Also, it is preferable to lock the injection needle 130-1within the housing 304-1 after a single injection to reduce exposure tothe contaminated needle. Additionally, it is preferable to only allowdisplacement of needle 130-1 after insertion of cartridge 116.Accordingly, a locking assembly 268A is provided to accomplish theforegoing.

The locking assembly 268A comprises member 268 as shown in FIG. 4Chaving a first end configured to be moved by pushing member 174 and asecond end configured to displace a ball 270 or other appropriatemovable locking device. With the pushing member 174 in the firstposition such that injection needle 130 is within the housing, groove272 of the pushing member 174 aligns with groove 274 such that ball 270can freely travel around the groove 274 of the pushing member. When vial102 is vertically oriented with the compressed gas above the liquid,thus being properly positioned for injection as shown in FIGS. 4B and4C, ball 270 rests in the bottom of groove 274 allowing the pushingmember 174 to displace the injection needle 130. If the vial 102 is notproperly positioned (for example, the assembly being upside down suchthat compressed gas would be injected, as shown in FIGS. 4E and 4F), theball 270 is positioned within grooves 272 and 274 to preventdisplacement of the pushing member 174.

The locking assembly 268A can be further configured to allowdisplacement of the pushing member 174 only after cartridge 116 isinserted. FIGS. 4G-4L illustrate this aspect of the invention. Moreparticularly, FIG. 4G is similar to FIG. 4C except cartridge 116 isshown outside of the housing 304-1. FIG. 4H is a sectional view takenalong line 4H-4H of FIG. 4G and shows member 276 of the lockingmechanism having a slotted portion 278 therein. Member 276 is slidablewithin the housing 304-1 and configured to be moved by insertion ofcartridge 116. The lower end of member 276 is positioned within grooves272 and 274 as shown in FIG. 4I. Thus, with member 276 in the positionshown in FIG. 4H, or before cartridge 116 is inserted into the housing304-1, the pushing member 174, and hence injection needle 130-1, isprevented from moving to the injection position.

When the cartridge 116 is fully inserted into housing 304-1 as shown inFIG. 4J, member 276 is moved downward as shown in FIG. 4K. As shown inFIG. 4L, this allows slotted portion 278 to align such that pushingmember 174 and hence injection needle 130-1 can be moved to theinjection position.

With the device 100-1 properly held by the user such that vial 102 isvertically oriented as shown in FIG. 4M, the user presses pushing member174 such that the injection needle 130-1 first extends out of thehousing 304-1, thus penetrating the skin of the person being injected.Continued pressing of pushing member 174 causes the second end 172 ofinjection needle 130-1 to puncture sealing member 170, thereby allowingthe pressurized reconstituted lyophilized drug 166 to travel from vial102 into the person being injected. It may take in the range of 10-30seconds to deliver the injection fluid. This pressing motion compressesspring 190 such that upon release of pushing member 174, the memberreturns to the original position, i.e., the needle 130-1 is withdrawnwithin the housing 304-1 and locked therein. Insertion of the pushingmember 174 into the housing 304-1 also moves in member 268 such thatball 270 is biased against the pushing member. This is shown in FIG. 4N.When the pushing member 174 is returned to the first position, the ball270 is positioned and held within groove 272 by member 268, therebypreventing displacement of the pushing member and hence the injectionneedle 130-1 after a single injection. This configuration is illustratedin FIG. 40. With the injection needle 130-1 locked within the housing304-1, the device 100-1 may be safely discarded.

FIGS. 5A-5C illustrate a drug delivery device 100-2 in accordance with apreferred embodiment of the present invention. More particularly, FIG.5A illustrates the device 100-2 with the cartridge 116 installed but notinserted or penetrated by any needle, and the vial 102 in place ready tobe inserted. FIG. 5B illustrates the inserted vial 102, while FIG. 5Cshows the subsequently inserted cartridge 116. At this stage, thediluent from cartridge 116 has been transferred to vial 102, resultingin a pressurized liquid in the vial. The device 100-2 is vigorouslyshaken to ensure proper mixing of the reconstituted lyophilized drug.The device 100-2 is now ready for injection. It should be noted that thehousing 304-2 advantageously includes a cutaway portion 254 which allowsthe user to visually inspect vial 102 to verify that the lyophilizeddrug 160 is thoroughly mixed with diluent 166 and to verify that vial102 is vertically oriented during injection to ensure air is not beinginjected into the injection site.

FIGS. 6A-6C are plan views of a similar device 100-3 corresponding toFIGS. 5A-5C, respectively. Accordingly, FIG. 6A illustrates thecartridge 116 installed but not punctured by needle 126-3. Vial 102,containing the lyophilized drug 164, is also shown ready to be insertedinto housing 304-3.

FIG. 6B shows the inserted vial 102 which is punctured by needle 124-3.Vial 102 pushes first against surface 178-3 of puncturing device 182-3and pushes device 182-3 downward before being pierced by needle 124.Pushing puncturing device 182 downward sets a spring which (as will beexplained in FIGS. 7A-7C) moves puncturing device upward such thatneedle 128-3 penetrates vial 102. Alternatively, the spring can bepreloaded. As shown, needles 124-3 and 126-3 are fluidly connected by amanifold 127 comprising a channel 129 or tube. Upon insertion ofcartridge 116, the rubber stopper is first pierced by needle 126, and ascartridge 116 is further inserted into the circular opening 176-3 ofhousing 304-3, the rubber stopper 118 is forced to the bottom ofcartridge 118, thereby forcing the diluent 166 through the manifold 127into vial 102. This also compresses the gas that was heretoforecontained in the vial 102 to a pressure sufficient for injection. Theresulting stage is shown in FIG. 6C. The device 100-3 is preferablyvigorously shaken to ensure proper mixing of the lyophilized drug 164.Now, the device 100-3 is ready to inject the reconstituted drug solution160 contained in the vial 102.

FIGS. 7A-7C illustrate partial perspective views of the device 100-2,100-3 shown in FIGS. 5A-5C and 6A-6C. More particularly, FIG. 7A showsthe pushing member 174-3 including an internal bore with member 252slidably contained therein. Member 252 fixedly supports injection needle130 which is in fluid communication with needle 128 via tube or channel120. Needle 128 shown in FIG. 7A has yet to pierce the rubber stopper112 of vial 102. Needle 128 is fixedly supported by puncturing device182. As the pushing member 174-3 is pressed toward the housing 304-3(i.e., in the direction of arrow 180), a first spring 190 is compressedallowing the member 252 to move downward until contacting the housing.This allows injection needle 130-3 to extend out of needle aperture 256in housing 304-3 to penetrate the skin of the person being injected. Thespring 190 is set such that it creates both axial and rotationalmovement. Only upon complete insertion of the vial 102 is the rotationalmovement of the spring enabled which in turn enables the puncturing ofthe vial 102. In the preferred embodiment, injection needle 130-3extends in the range of 5-12 millimeters out of the housing throughneedle aperture 256. The injection needle 130 partially extending out ofthe housing 304-3 is illustrated in FIG. 7B.

As the pushing member 174 is further pressed toward housing 304-3,spring 200, which is stiffer than spring 190, is compressed allowingridge 258 of pushing member 174-3 to contact puncture device 182. Thiscauses rotation of puncturing device 182 in the direction of arrow 186as shown in FIG. 7C, such that surface 178 no longer contacts the vial102. The spring 190 which, as described above, was loaded upon insertionof vial 102, now causes the puncturing device 182 to rotate in thedirection of arrow 184, thereby causing needle 128 to penetrate therubber stopper 112 of vial 102. This arrangement is illustrated in FIG.7C. The reconstituted drug 160 is forced by the compressed gas withinvial 102 through injection needle 130 into the person being injected ina time range of approximately 10-30 seconds.

FIGS. 8A-8E illustrate a drug delivery system 100-4 in accordance with apreferred embodiment of the present invention wherein the same referencenumbers refer to the same or similar elements. More particularly, FIG.8A illustrates the device 100-4 which includes housing 304-4 having afirst port or opening 176-4 for receiving cartridge 116 and a secondport or opening 262-4 for receiving vial 102.

Vial 102 containing the reconstituted drug 164 is inserted into thehousing 304, followed by the insertion of cartridge 116 containing thediluent 166. Again, a rubber stopper of the cartridge 116 is forced tothe bottom of the cartridge which forces the diluent under pressure intovial 102. This stage is shown in FIG. 8B. Advantageously, the housing304-4 includes a cutaway portion 400 such that vial 102 is substantiallyvisible during reconstitution and injection. This allows the user tovisually verify that the drug is properly reconstituted and that thevial 102 is vertically oriented during injection with the compressed gasabove the reconstituted drug.

FIG. 8C is a rear view taken of FIG. 8B and illustrates the injection ofthe reconstituted drug. More particularly, the pushing member oractuator 174-4 is pressed into housing 304-4 which forces injectionneedle 130-4 out of the housing and into the person being injected. Inthe preferred embodiment, the injection needle extends out of thehousing in the range of 5-12 millimeters. The reconstituted drug, influid communication with the vial 102, is transferred from the vial andinto the person being injected. FIGS. 8D-8F are isometric views of thedevice 100-4 in the stages shown in FIGS. 8A-8C, respectively.

FIGS. 10A and 10B graphically illustrate system characteristics of apreferred embodiment of the drug delivery device. To provide effectivedelivery of a specified amount of fluid and minimize patient discomfort,the system requires a sufficient fluid pressure in the delivery vialthat is manually actuated by the user within a short time period. FIG.10A shows the pressure (millibars) and weight (grams) characteristics ofthe system during a delivery period of about 30 seconds for a deliveryvolume of about 1.6 milliliters. FIG. 10B illustrates test results ofthe delivery of 1.6 milliliters into different animals using a singledrug delivery device for the same time period.

Referring to FIGS. 11A-11D, cutaway views of a preferred embodiment of adiluent container subassembly and a manifold, which may be used with thedrug delivery devices or with an ordinary syringe or other drug deliverydevices, are illustrated. The diluent container subassembly 300 includesa preassembled compression portion 310 which allows the user to hold thediluent container 312, which can be in the form of a compressible sealedbag, and insert it into a needle 314. The diluent container 312 containsabout 1 milliliter diluent and a controlled volume of gas, such as air,for example, and upon insertion into housing 304-6, is pierced by theneedle 314. During storage or shelf life, the diluent container 312 issized to allow for expansion of the container as a result of changes tothe environment. In addition, the compression portion 310 is used tocompress the exterior of the diluent container and apply pressure to thecontents of container during delivery of the diluent for mixing. Thediluent containers are formed from flexible, collapsible materials, forexample, polyethylene, polypropylene and nylon. The compression portion310 includes a slider element 316 and two longitudinally extending arms318, 320 extending therefrom. Two cylindrical drums 322, 324 are spacedbetween the longitudinally extending arms 318, 320.

FIG. 11A illustrates the diluent container subassembly 300 positioned inthe housing 304-6 of the drug delivery system in accordance with thepresent invention. FIG. 11D further illustrates the fully compressedstate of a preferred embodiment of the diluent container subassembly300. The slider element 316 of the compression portion 310 translates inat least one axis, for example, in the illustrated embodiment, it canmove up or down. The downward movement of the slider element 316 causesthe diluent container 312 to wrap around the cylindrical drum 324 whichcompresses the contents of the diluent container 312, thus forcing thediluent from the container 312 and through the needle 314 and into thevial 102. The movement of the slider element 316 is limited by an end oftravel position. At this end of travel position, the slider element 316may be locked by a locking mechanism which ensures that the diluentcontainer is kept compressed.

A manifold 330 includes two needles 314, 332 fixedly mounted at the endsof an extending member 334. The needles can also comprise a penetratingmember that is formed from an injection molded material such as medicalgrade polycarbonate or acrylic with the required level of rigidity topenetrate the vial or container. A channel 331 provides for fluidcommunication between the needles 314 and 332. Needle 314 pierces thediluent container 312 upon insertion of the container, while needle 332pierces the vial 102 upon insertion of the vial containing thelyophilized drug 164. In a preferred embodiment of the presentinvention, container 312 contains approximately 1 milliliter of diluentand a controlled volume of air which is forced into vial 102, resultingin a pressure inside vial 102 of approximately 2.25 bars. The pressureinside vial 102 results from forcing the controlled volume of air in thediluent container 312 into the rigid volume in the vial 102. Thus, thediluent 166 is forced into vial 102 to mix with the lyophilized drug 164contained therein. The entire assembly is preferably shaken to ensurethe reconstituted drug 160 is properly mixed in preparation forinjection. The vial 102 is vertically oriented during injection toensure air is not being injected into the injection site.

Referring to FIG. 11C, the injector needle 130-6 is shown in a firstposition within the housing 304-6. As described hereinbefore, theinjection needle 130-6 is in the range of a 24-28 gauge needle and ispreferably a “U” shaped needle having a second end 172-6 configured topuncture sealing member 170-6. An area 171 is located adjacent to thesealing member 170-6 and is in communication with the channel 331 asshown in 11B.

When the user compresses the button 305, it causes the needle 130-6 topenetrate the skin and the second end 172 to penetrate the sealingmember 170. The drug and diluent solution will flow from the needle 332,through the channel 331, and area 171 and to the user via the injectorneedle 130-6. As the user compresses the button 305, which is springloaded by spring 306, a pair of mating pawls 307, 308 fit together andprevent the button from being pulled out and the reuse of the device asshown in FIG. 11C.

FIGS. 12A-12B illustrate perspective views of a preferred embodiment ofthe diluent container subassembly 300 and provide further details of thecomponents of the compression portion 310. The cylindrical drum 324 isslotted such that the diluent container can be inserted therein. Thecylindrical drum 322 serves as a backing drum. Thus, the diluentcontainer 312 is typically inserted between the cylindrical drum 324 andthe backing drum 322. The drum apparatus 322, 324 moves in a rack andpinion gear apparatus 340. An end of travel position 342 in the rack andpinion gear apparatus 340 constrains the movement of the cylindricaldrum 324 at its end of movement position. This end of travel positioncorrelates with the end of the wrapping of the diluent container 312around the cylindrical drum and maximum compression of the contents ofthe container. A flange 344 can be used to hold the diluent container312 at the bottom of the subassembly 300. The diluent container 312 canbe sealed by means of heat welding techniques or ultra sonic techniquesto the flange 344 after it has been filled with the diluent. Thelongitudinally extending arms 318, 320 in the compression portion 310each comprise two members 350, 352, as shown in FIG. 12B. A cylindricaldrum is attached to each member. The two members 350, 352 are spacedapart from each other to accommodate the wrapping of the diluentcontainer on the cylindrical drum 324.

Referring to FIGS. 13A-13B, cutaway views illustrate an alternateembodiment of the invention similar to that shown in FIGS. 11A-11Dincluding a manifold 350. The manifold 350 has two needles 352, 354 forthe purpose of piercing the vial 102 and diluent container 312respectively. Once the diluent 166 and the controlled volume of air areforced to move into vial 102, the diluent mixes with the lyophilizeddrug 164 and results in the reconstituted drug 160 which is underpressure. Because the reconstituted drug is under pressure due to thecontrolled volume of air, it is forced through the needle 352 and intothe person being injected through a needle 351 that is actuated bymovement of pushing member 353. This embodiment of the device provides auser comfort as it does not have to be vigorously shaken to ensure thereconstituted lyophilized drug 160 is properly mixed in preparation forinjection. The controlled volume of air facilitates the mixing of thediluent and the lyophilized drug. The pushing member 353 displaces theinjection needle 351 between a first position within the housing 304 anda second position outside the housing, or in an injection state.

It is preferable to prevent displacement of the injection needle 351when the device 100-7 is not properly oriented, for example, upsidedown, in order to prevent the compressed gas in vial 102 from beinginjected. Also, it is preferable to lock the injection needle 351 withinthe housing 304-7 after a single injection to reduce and preferably toprevent the exposure to the contaminated needle. Additionally, it ispreferable to only allow displacement of needle 351 after insertion ofdiluent container 312. Accordingly, a locking mechanism comprisingmember 268 as shown in FIG. 4B is provided to accomplish the foregoing.The member 268 has a first end configured to be moved by pushing member353 and a second end configured to displace a movable locking device,substantially similar to the device shown in FIG. 4B.

With the device 100-7 properly held by the user such that vial 102 isvertically oriented, the user presses pushing member 353 such that theinjection needle 351 first extends out of the housing 304-7, thuspenetrating the skin of the person being injected. Continued pressing ofthe pushing member 353 causes the second end 355 of injection needle 351to puncture sealing member 357, thereby allowing the pressurizedreconstituted drug 166 to travel from vial 102 into the person beinginjected. It may take in the range of 10-30 seconds to deliver theinjection fluid. The pressing motion compresses spring 359 such thatupon release of pushing member 353, the member returns to the originalposition, i.e., the needle is withdrawn within the housing 304 andlocked therein.

Referring to FIG. 14A, a cutaway view illustrates a manifold of anotherpreferred embodiment of the drug delivery device 100-8 in accordancewith the present invention. The manifold 350 has two needles 352, 354for the purpose of piercing vial 102 and diluent container 312,respectively. A flange, substantially similar to the flange 127 shown inFIG. 6B, holds the septum or stopper 313 in place in the container 312.An extending member or communication chamber 356 which is in fluidcommunication with the needles 352, 354, has a membrane such as ahydrophilic membrane or barrier 360 disposed therein. It should be notedthat the hydrophilic membrane needs to be wetted before it functions tominimize or preferably prevent the flow of gas into a user's tissue. Thehydrophilic membrane allows gas, for example, air to pass freely till itcomes in contact with liquid and gets wet. Thus, when wet, no air suchas the controlled volume of air in the diluent container 312 can passthrough the hydrophilic membrane, preventing air from entering theuser's tissue. The presence of the hydrophilic membrane prevents riskscaused by any wrong use of the device 100-8 by the user such asincorrect positioning of vials or containers.

Referring to FIGS. 15A-15B, cutaway views illustrate another preferredembodiment of a manifold of the drug delivery device in accordance withthe present invention. The needle 352 pierces the vial 102 while needle354 pierces the diluent container 312. The needle 354 and channel 352 onspike 352A are in fluid communication. Diluent 166 moves from thediluent container 312 into vial 102, thus mixing with the lyophilizeddrug to result in a reconstituted drug. A channel 358 is incommunication with an area 361 sealed by a stopper 313. Channel 358 alsoincludes a hydrophilic membrane. Thus, upon the introduction of air tothe channel, the membrane expands in the presence of air and disallowsthe passage of air therethrough.

In use, the user presses the button 363 which first moves injectorneedle 130 into the users skin. Further movement of the button 363causes piercing member 172 to penetrate the stopper 313. This enablesliquid drug/diluent solution to move, via the air pressure in the vial102 through the injector needle 130 and the user's skin.

It should be noted that the embodiment illustrated with respect to FIGS.15A and 15B being more position independent, is not subject to airblocking the flow of liquids through the gas impermeable membrane untilall the drug solution has been transferred out of the vial 102. FIG. 15Ashows the position of channel 358 relative to channel 352. Thus, only ifthe vial 102 is completely filled with air would it pass into channel358. In contrast, the embodiment illustrated with respect to FIG. 14 andthe absence of the lower channel 358 is more position dependent and thussubject to air blocking the flow of liquids through the gas impermeablemembrane even while the drug solution is being transferred out of thevial 102.

Further, it should be noted that the delivery times of the drugs isdependent on the volume of vial which may be adjusted. The pressure isadjusted in part by adjusting the vial volume size. A large vial volumeof air relative to the drug would result in greater air pressure andfaster drug delivery.

In the preferred embodiments of the present invention the drug vials andthe diluent containers are shown as being inserted in the housing 304and aligned in the same direction along parallel axes. In thealternative, it is contemplated that the vials and containers may not bealigned in the same direction along parallel axes. The vials andcontainers may be inserted along two different axes that are oriented atoblique or orthogonal angles relative to each other.

Referring to FIG. 16 a cutaway view illustrates an alternate preferredembodiment of an injection device 236 in accordance with the presentinvention. The device 236 facilitates the sterilized injection of aprefilled cartridge or vial containing an injectable liquid, forexample, a vial containing a liquid drug 160. The device 236 includesfirst opening 161 for receiving vial 102 and a manifold 370 includingmember 372 sealingly engaged with the first opening 161. Member 372fixedly supports needle 374 and is supported by a collapsible volume,such as bellows 378, or any other device capable of injecting a fluidsuch as a gas upon being compressed. A check valve 380 ensures that theflow from the bellows is unidirectional, that is, the drug underpressure can not enter the bellows 378. The check valve 380 comprises atubular member 381 adapted to deliver gas, for example air, to the vial102. Air is moved out of the bellows and into the tubular member 332 bycompressing, the bellows 378. The check valve 380 allows the flow of airout of the bellows 378 and into the vial but disallows the reverse flowof air from the vial into the bellows. Air from the bellows 378 isforced up through needle 374 and into vial 102 applying pressure to thecontents of the vial 102. The liquid drug 160 is under pressure and isinjected into the user directly from the vial 102. The injection processis the same as discussed earlier with respect to embodiments in FIGS.13-15, in that the use of a U-shaped needle assembly is compressed intothe skin to activate injection. As discussed earlier, due to the natureof the hydrophilic material, a hydrophilic membrane 360 in the drugdelivery path minimizes and preferably prevents gas from being injectedinto the user.

Referring to FIGS. 17A-17C, cutaway views illustrate an alternateembodiment of the drug delivery device 100 in accordance with thepresent invention. The diluent container comprises a syringe 390. Whenpressure is applied to a plunger shaft 392, the diluent 166 is forcedout of the syringe 390 through the channel 398 and into the contents ofvial 102 via the needles 394, 396 which are in fluid communication witheach other through the member 398. Thus, the diluent 166 is provided tovial 102 under pressure and is mixed with the reconstituted drug toresult in a reconstituted drug solution ready for injection or deliveryunder pressure to a patient. The drug solution is delivered to a userusing a u-shaped needle assembly as disclosed with respect to FIGS.13A-13B, 14, and 15A and 15B. This syringe embodiment facilitates theuse of a standard prefilled container or cartridge containing only adiluent. The device is flexible and does not require special means ortraining.

The present invention includes alternate preferred embodiments ofinjection devices. FIGS. 9A-9F illustrate an injection device 236 whichfacilitates the sterilized injection of a prefilled cartridge or vialcontaining an injectable liquid, for example, a vial containing areconstituted drug 160. It is preferable to use a standard vial, forexample, a 2 milliliter vial, with this device 236. As shown in FIG. 9A,device 236 includes a first opening for receiving the vial 102 and amanifold including member 232 which is slidably and sealingly engagedwith the first opening. Member 232 fixedly supports needle 224 and issupported by a collapsible volume, such as bellows 228, or any otherdevice capable of injecting air upon being compressed. Needle 224 is insealed communication with the bellows 228 as shown in FIG. 9A. The vial102 is pressed into the housing 304-5 such that needle 224 pierces therubber stopper 112. This arrangement is shown in FIG. 9B.

The vial 102 is further pressed into the housing 304-5 which forcesmember 232 to compress bellows 228, thus forcing the air contained inbellows 228 up through needle 224 and into cartridge 116. Now, asillustrated in FIG. 9C, the cartridge 116 is under pressure for forcingthe drug 166 into the person being injected. The bellows or othercompression device can also be actuated by member 174-5.

As shown in FIGS. 9A-9F, device 236 is further provided with a pushingmember 226 for displacing the injection needle 130-5 between a firstposition within the housing 304-5 and a second position outside thehousing, or in an injection state. In the preferred embodiment a distalend of the injection needle 130-5 can extend out of the housing 304-5 inthe range of 5-12 millimeters. In this particular embodiment, theinjection needle 130 is preferably a “U” type needle having a second end250 configured to puncture sealing member 230. Sealing member 230, whichmay comprise any puncturable material such as butyl rubber, maintainsthe liquid in the upper part of housing 304. As the user presses pushingmember 226 into housing 304, the first end of the injection needle 130first penetrates the skin of the person being injected as shown in FIG.9D. Continued pressing of pushing member 226 into the housing 304 causesthe second end 250 of injection needle 130-5 to puncture sealing member230, thereby allowing the reconstituted drug 160 to travel fromcartridge 116 into the person being injected. This is illustrated inFIG. 9E. The pressing of the pushing member 226 into the housing 304-5compresses a spring such that upon release of pushing member 226, themember returns to the original position, i.e., the injection needle130-5 is in the first position within the housing 304-5 as shown in FIG.9F. This embodiment may be further provided with a locking mechanismsimilar to that disclosed in FIGS. 4A-4K. With the injection needlelocked within the housing 304-5, the device 236 may be safely discarded.

Further, FIGS. 18A-18C illustrate an injection device in accordance withan alternate preferred embodiment of the present invention. Moreparticularly, the drug delivery device 400 includes a straight needle402 having a lancet 404 disposed on a first end. A cavity 405 in theseptum 406 contains a liquid drug under pressure. The straight needle402 includes a side hole 407 disposed on the shaft. The second end 408of the straight needle is blocked. In operation, as shown in FIGS. 18A,18A-1, 18B and 18B-1, when the member 410 is moved forward toward thehousing 412, the injection needle 402 is displaced from a first positionin the housing 412 to a second position outside the housing such thatthe needle 402 penetrates the skin of the user. After the lancet 404penetrates the user's tissue, continued pressing motion of the member410 toward the housing causes the side hole 407 to be in fluidcommunication with the cavity 405 of the septum 406 creating a path forthe drug under pressure to flow into the user's tissue. The straightneedle punctures the septum 406 at two locations. As shown in FIG. 18C,as the member 410 is released, the injection needle is withdrawn withinthe housing 412.

More particularly, referring to FIGS. 18A-1, a 3 part ring structureincluding member 414, latch 416, gap 418 and spring 419, as shown inFIG. 18A provide an interlocking system. This safety mechanism whichincludes the members 410, 414, latch 416, gap 418 and spring 419provides an interlock to ensure against reuse of the drug deliverydevice 300 and exposure of needle 402 after the first use. Once themember 410 is compressed the mating ridges 413A and 413B come together.The ridges are angled on one side to allow ridge 413B to pass under 413Awhen member 410 is depressed against the housing 412. The ridges arepressed together when the force of the spring 419 moves member 410 awayfrom the housing 412. Because the ridges interface at a right angle tothe direction of movement of the member 410 they serve to preventfurther movement by the member and the needle 402. This mechanismensures that the device 400 is not reused.

FIGS. 19A-19F illustrate cutaway views of alternate preferredembodiments of systems which allow reconstitution of drug and subsequenttransfer into a drug delivery device in accordance with the presentinvention. Once the drug is made into a solution it may be transferredinto a user by means of direct injection as shown in FIG. 11, forexample, or into a drug delivery device such as an infusion pump,needleless injector or the like. The systems include a vial 420containing a predetermined volume of a drug and a vial 422 containing avolume of a diluent. The use of standard vials facilitate the use of thedrug delivery device by different drug suppliers.

An air source 424 maybe included for the delivery of drugs. With drugsof higher viscosity, the use of pressure becomes more important. Asillustrated in FIG. 19A, the sources of pressurized air can vary and mayinclude, but are not limited to, a compressed air delivery supply 426, achemical gas generator 428, a standard syringe 430 and a collapsiblevolume container, such as a bellow container 432. The air sourcesupplies the driving force to the diluent volume which moves the diluentsolution 434 into the standard lyophilized drug vial 420. Oncereconstituted, the liquid drug is transferred via the air separator,such as a hydrophilic membrane 436, to a drug delivery system. It shouldbe noted that spike 438 in the diluent vial 422 and spike 440 in thedrug vial 420 each have two paths. The spike 438 has a first path forcompressed air to enter the diluent vial 422 and a second path for thepressurized diluent 434 to be in fluid communication with the drug vial420. The spike 440 has a first path for the pressurized diluent to enterthe drug vial 420 and a second path for the delivery of the drugsolution into a drug delivery device. As discussed earlier, it iscontemplated that other drug delivery devices may be received into thissystem to receive the drug solution.

Referring to FIG. 19B, the air source is a compressed air canister 426.The compressed air canister typically is a standard addition fordomestic drug delivery devices. The user attaches the compressed aircanister 426 to the drug delivery system 450 and punctures a seal 452located in the compressed air canister. The air canister is then influid communication with the diluent vial 422 by means of channel 453.Air is released from the compressed air canister 426 and is introducedinto the diluent vial 422, which in turn forces the diluent solution 434to move into the drug vial 420 via channel 455. After reconstitution iscompleted, the liquid drug is ready to be transferred. The concentrationof the reconstituted drug can be controlled in this and otherembodiments by changing the quantity of diluent transferred toreconstitute the drug. A hydrophilic membrane 436 in the drug deliverypath minimizes and preferably prevents gas from being transferred to thedrug delivery device.

FIG. 19C shows a chemical gas generator 428 as the air source used inthis particular embodiment to deliver the diluent 434 under pressure tothe lyophilized drug vial. The chemical gas generator 428 includes achemical compartment 456 which typically contains two materials 458,460. The two materials 458, 460 can be two liquids or a liquid and asolid palette 460 that are separated during shelf life. It should benoted that the materials used in the chemical compartment 456 and thereaction that ensues during the mixing of the materials are safe andbiocompatible. Pushing a member 462, in the chemical compartment 456results in tearing of a seal 464, for example, aluminum foil, whichseparates the two materials 458, 460 during shelf life. The twomaterials are then in fluid communication and react to produce a gassuch as, for example, carbon dioxide. The chemical gas generator 428also includes a gas compartment 466 which is typically an air reservoirhaving a flexible enclosure 468. The carbon dioxide produced in thechemical compartment 456 due to the reactions enters the gas compartment466 and is accommodated in the flexible layers 468 that form the gascompartment. The movement of the flexible layers 470, 472 force the airor carbon dioxide into the diluent vial 422 through the air pathway 423.It should be noted that the gas compartment 466 has a double layer 470,472 comprising the flexible containment area. The two layers 470, 472provide for safety as if the air or gas generated as a result of thereaction in the chemical compartment does leak, it can be accommodatedbetween the flexible enclosure 468 of the gas compartment 466. Further,the gas compartment 466 is vented using a gas leakage pathway or ventport 474. The air that is released from the chemical gas generator 428enters the diluent vial 422 via the channel 423 which in turn forces thediluent solution 434 to move into the drug vial 420 via the channel 425.After reconstitution is completed, the drug is ready to be used, and istransferred to a drug delivery system such as one described with respectto FIG. 19B.

Referring to FIG. 19D, the air source used in this particular embodimentto deliver the diluent under pressure is a standard syringe 430 or anair reservoir. The syringe 430 is locked at an end of travel position.When pressure is applied to a plunger shaft 480 the air is forced out ofthe syringe 430 and into the contents of the diluent vial 422 throughthe needle 482 and needle 434 which are in fluid communication throughthe member 484. The diluent 434 is then forced into the drug compartmentor drug vial 420 via member 484 under pressure which provides for themixing with the lyophilized drug to result in a reconstituted drug whichis then ready for injection or delivery under pressure to a user. In analternate embodiment, a lever can be included to reduce the forcerequired for pushing the plunger member 480. The lever will increase thedisplacement and thus delivery of pressurized air to the diluentcontainer in this case, the drug solution may be injected as shown inFIG. 19D, the sectional of which is the same as shown and described inother needle assemblies, for example, shown in FIGS. 11, 13, 14, 15, 16,and 32 or transferred into a drug delivery device.

Referring to FIG. 19E, the air source used in this particular embodimentto deliver the diluent under pressure to the lyophilized drug is acollapsible volume container such as a bellow container 432. A checkvalve 488 or a one-way valve insures that the flow from the bellowcontainer 432 is unidirectional, that is, the drug or diluent can notenter the bellows. The check valve 488 comprises a tubular member 490adapted to deliver gas, for example air, to the diluent vial 422. Theresilient nature of the bellows is checked by the check valve 480 whichdoes not allow air to enter the bellows and thus reinflate the bellowsonce the bellows have been compressed and air has exited. Oncecompressed, air contained in the bellows 432 is forced through needle438 and into the diluent vial 422 via channel 491 applying pressure tothe contents of the diluent vial. The diluent solution 434 in turn, isdelivered under pressure to the drug vial 420 where the drug isreconstituted and can be transferred either by injection as describedabove or into a drug delivery device, as also described and shownrelating to the embodiment of FIG. 19A.

Referring to FIG. 19F, the air source used in this particular embodimentto deliver the diluent under pressure is cylinder 490. This embodimentis similar to the embodiment containing a standard syringe as describedwith respect to FIG. 19D. The plunger 492 is depressed to compress theair in the cylinder 490. The air is driven into the diluent vial 422through channel 494 which brings the cylinder and the diluent vial influid communication. The pressurized diluent in diluent vial 422 thenmoves into the vial 420 and mixed with the drug. The pressurized drugsolution is then ready to be delivered. This can either comprisedelivery to a drug delivery device as described with respect to theembodiment of FIG. 19A or injected as shown in the present embodimenthaving a straight needle assembly as shown and described in FIG. 18.

Referring to FIGS. 20A-20C, an alternate embodiment of the drug deliverysystem 498 in accordance with the present invention includes standardvial 500 containing a liquid drug 502. A volume of gas, for example air,contained in an air chamber 504 is introduced in the standard liquiddrug vial 500, creating air pressure above the liquid drug which allowsfor delivery of a liquid drug under pressure. The usage is positiondependent, that is the delivery of the liquid drug, is performed withthe standard vial 500 in a vertical position. In addition, a hydrophilicmembrane minimizes or preferably prevents the introduction of the extravolume of air into the user's tissue.

In use, as shown in FIG. 20A, the standard vial 500 containing theliquid medicament 502 is inserted into the drug delivery device 498 inaccordance with the present invention. An air chamber 504 is providedwhich upon insertion of the drug vial 500 and the puncturing of the seal506 of the vial, is in fluid communication with the drug vial. Onceinserted, the lip 505A of a standard vial 500 is locked into position bymeans of a pair of arms 505 having ridges 507 projecting inwardlytherefrom. The injector system is the straight needle 402 embodiment asdisclosed in FIGS. 18A-18C. Once the air from the air chamber isintroduced into the standard drug vial 500 the liquid drug ispressurized and is ready to be injected using the injector systemdescribed with respect to FIGS. 18A-18C. After injection into the user'stissue, the needle is retracted automatically. The drug delivery device498 is then disposed.

Referring to FIG. 21, an alternate preferred embodiment of a drugdelivery system 510 which uses standard vial 500 containing a medicamentis disclosed. A plunger 512 is included in the drug delivery device 510.In order to reduce forces which are required to insert the standard vial500 in the drug delivery device 510. In an alternate embodiment, thedrug delivery system 510 can have a compact configuration without aplunger. Snaps 514 lock the standard vial 500 into position. Snaps 516hold the end portion of the vial having the seal 506 in place to ensurethat the spike 518 pierces the seal 506 of the vial 500 before the vialis moved in the downward direction. Air in the air chamber 520 isdelivered to the vial 500 when the air is compressed and displaced bythe downward movement of the vial 500. The liquid drug under pressure isdelivered to an injector using tubing 522. A hydrophilic membrane 524minimizes or preferably prevents gas from entering the user's tissue.The injector system used can be similar to one described with respect toFIGS. 18A-18C. The member 410 is moved to displace the injection needle402.

Referring to FIGS. 22A-22E, the views illustrate an alternate preferredembodiment of the drug delivery system 530 in accordance with thepresent invention. This particular embodiment may be used as areconstituted system and a drug delivery system and includes two vials532, 534 a first containing a diluent 533 and a second containing thelyophilized drug 535. In addition, there is an air delivery system forpressurizing system, such as a built-in air cylinder 533 in fluidcommunication with the diluent vial 532 which is disposed between thelyophilized drug vial 534 and the diluent vial 532. Air is pushed intothe diluent vial 532 forcing the diluent 533 from its vial into thelyophilized drug compartment or vial 534. After reconstitution iscompleted, the liquid drug is ready for injection. A hydrophilicmembrane is used as an air separator to minimize or preferably preventthe entry of air into the user's tissue. This particular embodiment usesa straight needle 402 injector system as described with respect to FIGS.18A-18C. Additionally, a positioning interlock, such as the mechanism,described with respect to FIGS. 2A-2B is used. Further, in an alternateembodiment, the air cylinder can be replaced with a standard syringe tobe the air source as shown in FIGS. 22D and 22E. A check valve (as shownin FIG. 16) disposed in the air inlet between the syringe and manifoldis included in the embodiment containing the syringe. The drug deliverysystem of the present invention is used to deliver an accurate volume ofa drug solution. The predetermined volume can be delivered usingdifferent methodologies. A first embodiment controls the dose bychanging the height of the outlet spike 535 in the liquid drug vial 537as shown in FIG. 23A, i.e. the higher the spike, the lesser is theamount of drug transferred out of the vial 537. The spike is adjusted bymeans of threads 539 upon which the spike rotates or upon which itsealably slides. This can be used for to transfer or to inject the drugsolution. Another preferred embodiment which increases the accuracy ofthe volume of drug delivered uses the residual drug volume as aparameter to indicate the volume delivered. One way of controllingdelivered drug solution volume is to use the assembly shown in FIG. 23B.After the drug is pushed in solution in vial 102 the solution may bepulled into cavity 541 by piston 555. The cavity 541 has indicationsthereon to aid the user in determining the proper volume. At the desiredlevel, the piston is stopped. The drug solution is then transferred fromthe cavity 541 either via a needle into a user or into a drug deliverydevice. Yet another embodiment to provide an accurate volume of drug isdisclosed with respect to FIGS. 24A-24C and FIG. 25. The reconstitutionsystem having the vial containing the reconstituted drug is essentiallyused as a filling station by a detachable delivery device, for example,a standard syringe or a pen type pump.

Referring to FIGS. 24A-24C a position independent injector system 540 isillustrated. The drug 545 is reconstituted similar to the descriptionprovided with respect to earlier systems such as illustrated in FIG.19F. After the drug has been reconstituted it can be aspirated by aconventional standard syringe 542 for the exact dose required. Theaccuracy using this method is about +/−5%. The fluid level in the cavity550 is controlled by adjusting the pressure and geometry of the device540. The needle is held in place by the elastomeric septum or stopper552. In use, once the reconstituted drug is aspirated into the syringe542 by moving plunger 548 which moves the stopper 554 upwards allowingthe syringe 542 to be filled with the liquid drug, the syringe 542 isremoved from the drug delivery device 540. The accuracy of the volume ofthe liquid drug delivered is determined by the scale on the syringe. Theuser then injects the drug and disposes of the syringe by one of severalpotential ways. One of the ways of disposing the syringe is by attachingthe syringe to the open cavity 550 left in the drug delivery device 540.A second way is by securing the needle 547 prior to disposing thesyringe by locking it with a piece of plastic tubing. The system 540 andprocedure used is free of air inclusions and does not require an airseparator. The syringe needle 547 is placed in a closed cavitypenetrating a septum 544 and thus allows for fluid communication betweenthe needle 547 and the reconstituted drug. The volume of the closedcavity is designed to ensure the availability of the liquid drug to theneedle 547 under controlled pressurized conditions. The position of thesyringe piston 548 is fixed under pressurized conditions and the dose ismanually aspirated from the syringe.

Referring to FIG. 25 an alternate preferred embodiment of the drugdelivery system 540 as described in FIGS. 24A-24C is illustrated. Thereconstitution stage is similar to the one described with respect toFIGS. 24A-24C. However, the injector system including an attachabledelivery device is different. The user dials or tunes the required doseusing a pen type pump 560 that includes a dial 562 that is inserted intothe drug delivery device. The dialing process retracts a floating pistonwhich moves upward and creates an internal pressure which provides foraspiration of the reconstituted drug. A trigger 564 releases a preloadedspring to push the floating piston. Thus aspiration occurs by dialingthe dose into the pen-type injector. Once the pump 560 is filled asindicated by an indicator 566, it is disconnected from the fillingdevice. Injection and disposal of the pump is performed afterdisconnection with a process similar to the process described withrespect to FIGS. 2A-24C.

FIGS. 26A-26D are perspective views of a drug transfer system having adrug delivery device 510 in accordance with the present invention. Adiluent vial is inserted in a cavity 572 and a lyophilized drug vial isinserted in cavity 574. A cavity 576 accommodates an air pressurizationsystem to deliver drugs having a low level of viscosity. Further, thedrug transfer system includes an access 578 to receive a drug deliverydevice. The drug is transferred thereto via a needle 580.

FIGS. 27A-27C are cutaway views of a preferred embodiment of a transfersystem 600 in accordance with the present invention. Once pressurized bythe air in cavity 603, the liquid drug from vial 602 is transferred to adrug delivery device 604 via an extension 606. The liquid drug flows outof the vial 602 through spike 608 and through the tubing 610 into theneedle 616 which is received into the drug delivery device 604.

Referring to FIG. 27B, the drug delivery device 604 is attached to thetransfer system 600. The filling process continues until the entire druglevel reaches the outlet 604A (shown in phantom in FIG. 26B) of thedevice 604. At this point the filling process is completed. It should benoted that during the filling process, if the user stops pushing thevial 602 into the transfer system 600 the drug may drain into thecylinder 614. This is prevented by getting the friction forces higherthan the impedence of the tubing 610 to the drug flow. In thealternative, it is also possible to dispose a one-way valve at the endof the tubing 610. Once the drug delivery device 604 is filled with aliquid drug, it is disconnected from the transfer system 600. Anyresidual drug in the system 600 can stay protected, and the needle 616is retracted and as described earlier with respect to the needle lockingmechanisms is secured in the cover 606, and cannot be reexposed to causeharm or injury.

FIGS. 28A-28C are cutaway views of the operation of another preferredembodiment of a drug delivery system 630, in particular of a positionindependent injection system in accordance with the present invention.In this embodiment, the injection system 630 is position independent,that is the injector is not required to be in a vertical position duringthe injection process. Referring to 28A, the drug delivery system 630includes a vial 632 containing the liquid drug 634. The liquid drug 634flows through the spike 636 along a tube 644A into a cavity 652. Thespike includes two paths, one path 642 for delivering pressurized airinto vial 632 from chamber 641 and another path 644 to deliver theliquid drug to the user via a needle 664. The liquid drug exits from thepath 644 and travels along tube 644A disposed at the bottom of thespike. A one-way valve 638 insures the unidirectional flow of the liquiddrug 634 into the cavity 652A. Spring 640 holds piston 656 within thecavity 652. A floating piston 650 moves in the cavity 652. A seal 654 isincluded in the floating piston. Member 660 rests atop a needle assembly664A. Member 660 is hingedly connected to member 662. Member 662 has afinger 662A. Prior to use, the finger 662A rests within an aperture 662Bof the housing 660A. The notch 658 is the end of travel position for thepiston 656.

The path 642 from the air chamber 641 to the vial 102 pressurizes thevial by delivering air thereto. The air chamber 641 is depleted of airwhen the vial is moved downward. As the vial moves downward, a member641A sealably slides within the walls of the chamber and forces the airinto the vial. The member 641A is prevented from leaking air out of thechamber by the seal 641B.

In use, when vial 632 is pushed into the device 630, air from the cavity641 enters into the vial 632 and pressurizes the liquid drug. This drug634 under pressure flows via path 644 through the one-way valve 638 intothe left side of the cavity 652. Pressurized air pushes the floatingpiston 650 to the right side of the cavity 652. The floating piston 650moves until the position of the notch 658, which is the end of travelposition for the piston 656 and thus for filling of the cavity 652.Thus, as illustrated in FIG. 28B, an accurate volume of liquid drug isfilled in cavity 652 and the device 630 is ready to be used.

As illustrated with respect to FIG. 28C, once the member 660 isdepressed, it causes the needle 664 to move downwardly outside thehousing 660A and into the user's tissue. Member 662 is hingedlyconnected to member 660. When 660 is depressed, it causes member 662 tomove upwardly disengaging the finger 662A from the aperture 662B andenables the spring 640 to return to a less compressed state. As it does,the spring 640 forces the piston towards the opposing end of the cavity652. This causes the liquid drug therein to move via channel 652A andneedle 664 into the user's tissue, the piston 656 is released due to themovement of member 662 in the upward direction. The piston 656 moves tothe left. The floating piston 650 is under pressure and moves the liquiddrug in cavity 652 through the injector needle 664 and into the user. Itshould be noted that after delivery of the liquid drug, the position ofthe floating piston 650 depends on the load on the spring 640. Toprevent the flow of residual drug under pressure, the spring 640continues to be in a preloaded state. The seal 654 is pushed to the leftside of the cavity 652 under pressure of spring 640 to seal against theexit of the pressurized residual drug via the channel 652A. Althoughdisclosed as having a pushing spring 640, other mechanisms may beincluded in the injector system to result in a position independentinjector.

Referring to FIG. 28D, a cutaway view of a spike 636 which brings theliquid drug 634 in fluid communication with the injector system isillustrated. The spike 636 penetrates the septum 639 of the vial 632when the vial is inserted into the cavity 640. The spike functions as apiston 641A and is sealably and slidably movable by means of the seal641B within the interior walls of the chamber 641. As describedhereinabove, the spike also consists of two paths, an air inlet 642 anda drug outlet 644. Once the vial 632 is inserted, pressurized air entersthe vial 632 from an air chamber 641 and forces the liquid drug 634 viaa flexible tube 644A to the injector system. The filling process for theinjector system in a preferred embodiment is preferably done under amaximum pressure gradient of 0.3 bar. This includes a margin forexample, priming at an altitude of 5,500 feet and is the maximumexpected back pressure.

FIGS. 29A and 29B illustrate partial cutaway views of another preferredembodiment of the drug transfer system 670 in accordance with thepresent invention. The drug vial 672 containing the liquid drug 674 isinserted into a cavity 676. A spike 678 provides air into the liquiddrug vial 672 for pressurization of the drug 674 and additionally thespike provides for an outlet for the liquid drug to be delivered to adrug delivery system 680. The drug transfer system 670 is in fluidcommunication with the liquid drug vial 672 through a flexible tubing682 and a needle 684. A hydrophobic membrane 686 is disposed in theflexible tubing 682 to prevent the transfer of air into the drugdelivery system. This hydrophobic membrane 686 prevents back flow. Theair to pressurize the liquid drug 674 is provided by air in thereservoir 675. Further, a latch mechanism 688 secures the vial 672 tothe detachable delivery system 680 during a filling process.

Referring to FIG. 29A-1, an enlarged view of the interface between thedrug transfer system 670 and the detachable drug delivery device 680 isillustrated. A hydrophobic membrane 692 is disposed at the interface forblocking the flow of the drug once the drug delivery device 680 isfilled. An elastomeric cover 694 is disposed around the needle 684 forprotection against the needle 684. Tab 693 is pulled off to remove thehydrophobic membrane 692 prior to use of the device 680.

In operation the liquid drug vial 672 is pressed into the cavity 676which causes the air in the reservoir 675 to be compressed and enter theliquid drug vial 672. Air is prevented from leaking out of the cavity675 by means of seal 685. The liquid drug 674 is pressurized anddelivered through the spike outlet 690. Residual air from the airreservoir 675 is vented from an opening in the latch mechanism 688 oncethe latch is disengaged from the drug delivery device at the end oftravel of the vial and subsequent end of the transfer process.

Referring to FIGS. 30A and 30B, the two piece 696, 697 construction ofthe manifold in accordance with the present invention is illustrated.The manifold is a biocompatible material such as, for example,polycarbonate or acrylic or pvc molding having a gas impermeablemembrane 698 welded in the part 696. The two pieces 696, 697 areultrasonically welded together.

Referring to FIGS. 31A-31E, perspective views illustrate an alternatepreferred embodiment of a drug delivery system 700 in accordance withthe present invention. This particular embodiment maybe used with thereconstituted drug delivery system and includes two vials 702 and 704, afirst containing a diluent and a second containing a drug that needs tobe reconstituted. In addition there is a pressurizing system, such as abuilt-in cylinder 706 in fluid communication with the diluent vial 702.The built-in pressurization system such as the cylinder 706, is disposedbetween the lyophilized drug vial and the diluent vial. A plunger 708 isslidably received into the cylinder 706 to provide the necessary airpressure to effect drug transfer. Air is pushed into the diluent vialforcing the diluent from its vial into the lyophilized drug compartmentor vial 704. As discussed previously, a hydrophilic membrane is used asan air separator to minimize or preferably prevent the entry of air intothe user's tissue. In use, a diluent vial is inserted into the drugdelivery system 700 followed by the insertion of a drug vial. Theplunger 708 is pushed downwards to pressurize the air in the cylinder706 and deliver it to the diluent vial 702. Once the diluent solution ispressurized it is delivered to the drug vial 704 to reconstitute thedrug. Pressing the knob mechanism 710 displaces an injection needlewhich is used to inject the reconstituted drug into a user tissue. Thedepression of the knob mechanism and subsequent injection is similar tothat described earlier with regard to either the straight needleassembly shown in FIG. 18 or the U-shaped needle shown in FIGS. 11, 13through 17.

Referring to FIGS. 31F and 31G, two preferred embodiments 711, 713 whichprovide a visual indication of device orientation are illustrated. Thevertical indicators 711, 713 are shown as being disposed on the top ofthe plunger 708, however their location can vary to provide appropriatevisual indication. In the first embodiment of the vertical indicator711, a metal ball 714 rests upon a curved surface having visualindicators or scale 712 thereon. The ball 714 is enclosed within a clearcasing 712A. The positioning of the ball 714 in the middle of the scaleis an indication of vertical orientation. In the second embodiment 713of the vertical indicator, an air bubble 716 disposed in a liquid 718enclosed within a clear housing 718A is used as the visual indicator oforientation with respect to the scale 719. The positioning of the airbubble 716 in the middle of the scale is an indication of verticalorientation.

Referring to FIGS. 32A-32E, perspective views illustrate a furtheralternate embodiment of the drug delivery system 720 in particular areconstitution and injection system, in accordance with the presentinvention. In this embodiment the reconstitution of the drug occurs bythe mixing of the diluent solution with the drug. A separatepressurization system for the diluent is not required for thisparticular embodiment and can only be used with low viscosity drugs. Inuse, the knob 730 is moved in a counter clockwise direction to begin thereconstitution process of the drug which opens a pathway connecting thediluent with the drug. The knob 730 is turned from a non-use position(as indicated when notches A and B align) to a ready to use position asindicated with the alignment of notches B and C. At this point, the knob730 may be depressed and the solution injected. The internal pressure ofthe diluent vial and gravity cause the diluent to transfer to the vialcontaining the drug. Further movement of the knob or dial 730 activatesan injection needle which interfaces with the user's tissue to deliverthe reconstituted drug. Again, the injection assembly is similar to theembodiments shown in FIGS. 11, 13-17.

Referring to FIGS. 33A-33I, cutaway views of preferred embodiments ofthe drug delivery system emphasizing the interlocks disposed to providefor a safe system are illustrated. Referring in particular to FIGS. 33Aand 33B, the interlocks as required during shelf life of the drugdelivery device 750 are illustrated. The end of the cylinder 752 has abiasing lip 766 extending outward to matingly fit with wall 758 and thelip must be flexible enough to bend with the pressure of wall 758 whenvials are inserted in the assembly. During shelf life the cylinder 752is secured by latch 754 and mating lip 756. This mating fit prevents themovement of the movable cylinder 752 in the vertical direction prior touse. As previously described, the cylinder 752 provides pressurized airto the drug delivery system 750. The movement in the downward directionof the cylinder 752 is minimized or preferably prevented by holding thelatches 754 and 756 on the wall 758. An upward movement of the cylinder752 is prevented by latch 754.

Referring to FIG. 33C, the next step includes the insertion of the vials760 and 762 into the device 750. Only after the insertion of both vials760, 762 is the cylinder 752 free to be pushed in the verticaldirection. The insertion of the vials forces the lip 766 inward enablingit to clear the wall 758 and thus enable the cylinder 752 to movedownward. In addition, the latches 754 secure the vials in the device750.

Referring to FIGS. 33D and 33E, the interlocks that play a role once thecylinder 752 is pushed as illustrated. The cylinder 752 is pusheddownward until the end of travel position and is locked by the mating oflip 766 and interlock element 768. Again, as described above with regardto pre-use, the lip 766 moves downward and catches on element 768 andmoves to a radially expanded position which prevents the cylinder fromtravelling upward again. A locking element 768 keeps the cylinder in thebottomed out position. The element 768 is formed as a part of the wall758.

In the area where the drug solution is injected there is a pushingmember that moves in a relative perpendicular fashion to the directionof travel by the cylinder. A ball 772 is positioned prior to use withinthe housing to prevent depression of the member 776. When the cylinderis fully depressed, the lip 766, pushes a member 770 which allows theball 772 to drop into a groove 774 making the movement of the pushingmember 776 possible only if the device is in a vertical orientation.

Referring to FIGS. 33F and 33G, during the injection process differentinterlock elements insure the safe use of the drug delivery system. Asthe pushing member 776 is depressed, which is only allowed if the drugdelivery system 750 is in a vertical orientation, the horns 778 spreadthe latch 780 which allows the member 770 to press the ball 772 in theupward direction. Note the pushing member 776 is already pushed toexpose the needle 782.

Referring to FIGS. 33H and 33I, the interlocks during the phase ofdisposing of the drug delivery device which follows the injection phaseare illustrated. The pushing member 776 is released by the action of thespring 777 pushing the member 776. Since the movement of the ball 772was limited by the body of the member 776, with the release of themember 776, the ball 772 can now move back into the groove 774 as it isassisted by the pressure applied by the rear shell latch 780. This locksthe pushing member 776 into position thereby preventing further use ofthe drug delivery device 750.

Referring to FIGS. 34A through 34D, a preferred embodiment of the drugdelivery device having an end of delivery indicator is illustrated. Asdiscussed previously with respect to preferred embodiments of the drugdelivery system of the present invention, the drug delivery system isactivated by pressurized gas, for example, air. The air forces the drugto the injection site by pressurizing the drug. A hydrophillic membraneminimizes and preferably prevents the passage of air into the user'sbody. The hydrophillic membrane is disposed in the drug path to theuser's tissue. Once wetted, the hydrophillic membrane allows liquid drugto proceed into the user's tissue and stops the passage of air into theuser's tissue. In order to insure the effectiveness of the membrane, thehydrophillic membrane has to become wetted. To enhance the effectivityof the drug delivery device, a hydrophobic membrane is also positionedin the drug path. Referring to the FIGS. 34A and 34B, an inlet 800 whichprovides the liquid drug 802 into a cavity 803 has both a hydrophobicmembrane 806 and a hydrophillic membrane 810 disposed therein. Thehydrophobic membrane 806 allows air to pass, but stops liquids. On theother side of the cavity 803 the hydrophillic membrane 810 allows liquiddrug to pass while stopping the flow of gas. At one end of thehydrophobic membrane 806 a flexible elastomeric diaphragm is disposedthat acts as an indicator once filled with gas, for example, air. Themembrane being flexible, once filled with air gives an externalindication for end of delivery. The presence of air occurs only once theliquid drug has been delivered. It should be noted that the hydrophillicmembrane 810 is disposed close to the injection site as it allows liquidto go through to the injection site minimizing or preventing the flow ofgas into the user's tissue. FIG. 34D illustrates a manifold structureutilizing the end of delivery indicator 804 built into the manifold. Theseptum 814 surrounds a cavity containing the liquid drug. The spikes 816and 818 interface with the elastomeric stoppers of vials containing adiluent and a medicament.

FIG. 35 graphically illustrates the delivery profile from a high volumevial having no additional air pressure in the vial. The profileillustrates pressure (in millibars) versus time (in seconds). Theinitial pressure in the vial is in the order of about 300 millibarswhich decreases during the delivery process to approximately 0 millibarsat the end of delivery process. This is in contrast to the pressure in avial that initially contained approximately 3 milliliters of air asillustrated with respect to FIG. 33. As a result, there is no residualair pressure in the vial once delivery is complete. The delivery processspanned a time period of approximately 86.4 seconds.

FIG. 36 graphically illustrates delivery duration and delivery pressurewith respect to an air volume in a vial. Three different profiles areillustrated with a first one 830 which is indicative of the pressure (inmillibars) before delivery, a second profile 832 indicative of theresidual pressure of the delivery and a third profile 834 which isindicative of delivering 0.95 ml of a liquid drug over a time span ofabout 8 seconds.

FIG. 37 is a graphical illustration of the delivery parameters for aninjection of a liquid drug having no additional air in the vial. Asdelivery of the drug occurs, the pressurization within the liquid vialdecreases over the approximately 17 seconds of delivery. These curvesillustrate test results of the delivery process of approximately 1 gramof liquid drug using a single drug delivery device for the same timeperiod.

FIG. 38 illustrates test results showing the air pressure gradient onhydrophilic membranes used to minimize or preferably prevent the entryof gas for example, air into the user's tissue. The test results provemembrane safety to insure that the membrane can withstand the pressuresin the order of 2,700 millibars for a time duration of about sixminutes.

FIG. 39 graphically illustrates the performance of a drug deliverydevice in accordance with the present invention. Three delivery profiles840, 842, 844 (in ml) vs. time (in seconds) are illustrated for areconstituted lyophilized drug delivery system. The system includes a0.45 micron pore size hydrophilic membrane to minimize or preferablyprevent the flow of gas into the user's tissue. This particular poresize of the membrane provides an adequate particle filter and alsoallows the shortest time to deliver the drug to the user's tissue.

FIG. 40 is a flow chart that describes the methods for delivery of alyophilized drug in accordance with the present invention. The methodsinclude the step 899 of inserting the drug and diluent containers intothe drug delivery device. Further per step 900, the method includesactivating a pressurized air source which in turn is followed by thestep 902 of pressurizing a diluent solution in a diluent vial. Asdiscussed with respect to FIGS. 19A-19F, the pressurizing can beprovided by subsystems which include but are not limited to a compressedair supply, a chemical gas generator, a collapsible volume air supply, astandard syringe or cylinder.

The methods further include the step 904 of delivering the pressurizeddiluent solution to the lyophilized drug vial. The lyophilized drug isreconstituted per step 906 as a result of the mixing of the diluent withthe lyophilized drug. The methods further include the step 908 ofproviding the liquid drug to an injector system or transferring theliquid drug to a detachable delivery device. The liquid drug is theninjected into a user's tissue per step 910. The injection needle is thenmoved to a safe storage position per step 912.

FIG. 41 is a flow chart that describes the methods for delivering aliquid medicament in accordance with the present invention. The methodsinclude the step 913 of inserting a drug container such as a vial intothe drug delivery system. Further, per step 914 the method includesactivating a pressurized air source for low viscosity drugs. It shouldbe noted that for drugs with a high level of viscosity no pressurizationmay be required. The method then includes the step 916 of pressurizingthe standard drug vial. The pressurized liquid drug is transferred to adrug delivery system such as an injector system, or detachable deliverydevices per step 918. The liquid drug is then injected into the tissueof a user per step 920. The method further includes the step 922 ofretracting the injector into a safe storage position.

It is further appreciated that the present invention may be used todeliver a number of drugs. The term “drug” used herein includes but isnot limited to peptides or proteins (and mimetic thereof), antigens,vaccines, hormones, analgesics, anti-migraine agents, anti-coagulantagents, medications directed to the treatment of diseases and conditionsof the central nervous system, narcotic antagonists, immunosuppressants,agents used in the treatment of AIDS, chelating agents, anti-anginalagents, chemotherapy agents, sedatives, anti-neoplastics,prostaglandins, antidiuretic agents and DNA or DNA/RNA molecules tosupport gene therapy.

Typical drugs include peptides, proteins or hormones (or any mimetic oranalogues or any thereof) such as insulin, calcitonin, calcitonin generegulating protein, atrial natriuretic protein, colony stimulatingfactor, betaseron, erythropoietin (EPO), interferons such as α, β or γinterferon, somatropin, somatotropin, somastostatin, insulin-like growthfactor (somatomedins), luteinizing hormone releasing hormone (LHRH),tissue plasminogen activator (TPA), growth hormone releasing hormone(GHRH), oxytocin, estradiol, growth hormones, leuprolide acetate, factorVIII, interleukins such as interleukin-2, and analogues or antagoniststhereof, such as IL-1ra; analgesics such as fentanyl, sufentanil,butorphanol, buprenorphine, levorphanol, morphine, hydromorphone,hydrocodone, oxymorphone, methadone, lidocaine, bupivacaine, diclofenac,naproxen, paverin, and analogues thereof; anti-migraine agents such assumatriptan, ergot alkaloids, and analogues thereof; anti-coagulantagents such as heparin, hirudin, and analogues thereof; anti-emeticagents such as scopolamine, ondansetron, domperidone, metoclopramide,and analogues thereof; cardiovacular agents, anti-hypertensive agentsand vasodilators such as diltiazem, clonidine, nifedipine, verapamil,isosorbide-5-monotritate, organic nitrates, agents used in treatment ofheart disorders, and analogues thereof; sedatives such asbenzodiazepines, phenothiazines, and analogues thereof; chelating agentssuch as defroxanune, and analogues thereof; anti-diuretic agents such asdesmopressin, vasopressin, and analogues thereof; anti-anginal agentssuch as fluorouracil, bleomycin, and analogues thereof; anti-neoplasticssuch as fluorouracil, bleomycin, and analogues thereof; prostaglandinsand analogues thereof; and chemotherapy agents such as vincristine, andanalogues thereof, treatments for attention deficit disorder,methylphenidate, fluvoxamine, bisoprolol, tacrolimus, sacrolimus andcyclosporin.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the spirit and scope of theinvention as defined by the appended claims. For example, some of thefeatures of the position independence can be used in connection withreconstitution combination systems, transfer systems or injectionsystems. Likewise interlock features may be used with any of theaforementioned systems.

What is claimed is:
 1. A fluid injection device comprising: a housinghaving a penetrating member aperture; a first port in said housing thatreceives a first container that contains a solid compound for injection;a second port in said housing that receives a second container thatcontains a fluid to be mixed with the solid compound in the firstcontainer to form a reconstituted drug to be transferred from the firstcontainer; a first channel that provides fluid communication between thefirst and second containers; a first penetrating member movable from astorage position in the housing to an injection position extendingoutside the housing through the aperture; a mixing device that mixessaid fluid with said solid compound, said mixing device comprising: asecond penetrating member fixed to said housing and that penetrates saidsecond container; a third penetrating member fixed to said housing andthat penetrates said first container, said second and third penetratingmembers being in fluid communication with each other via said firstchannel; and a compression element in said housing that displaces thefluid in said second container; and a fourth penetrating memberpositioned within said housing and that penetrates said secondcontainer; and a second channel that fluidly connects said first andsaid fourth penetrating members.
 2. The device of claim 1 furthercomprising a handle member pivotally attached to said housing and thatactuates said fourth penetrating member to penetrate said firstcontainer.
 3. A method of fluid injection comprising the steps of:providing a housing member having a penetrating member aperture;providing a first port in said housing that receives a first containerthat contains a solid compound for injection; providing a firstpenetrating member fixed to said housing and configured to penetratesaid first container; inserting a first container in said housing;providing a second port in said housing that receives a second containerthat contains a fluid to be mixed with the solid compound to form aninjectable fluid; providing a second penetrating member fixed to saidhousing and configured to penetrate said second container; inserting asecond container in said housing; providing a first channel in fluidcommunication between the first and second containers; fluidlyconnecting said first and second penetrating members via said firstchannel; providing a third penetrating member that is movable between astorage position within said housing and an injection position outsidesaid housing via said penetrating member aperture; providing a fourthpenetrating member positioned within said housing and configured topenetrate said second container when displaced; fluidly connecting saidfirst and fourth penetrating members via a second channel; displacingsaid third and fourth penetrating member; and injecting said injectablefluid at an injection site with said third penetrating member extendingthrough said penetrating member aperture and into the injection site. 4.The method of claim 3 further comprising the step of biasing said thirdpenetrating member in the storage position.